Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR
Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR
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DOI：
10.1126/science.aay9813
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发表时间：
2020-02-21
期刊：
影响因子：
56.9
通讯作者：
Kruse, Andrew C.
中科院分区：
文献类型：
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作者：
Wingler, Laura M.;Skiba, Meredith A.;Kruse, Andrew C.
G蛋白偶联受体(GPCRs)偏向激动剂优先激活下游信号通路的一部分。在这项工作中，我们介绍了血管紧张素II 1型受体(AT1R)(2.7到2.9埃)与三种不同偏向的配体结合的晶体结构：平衡的内源性激动剂血管紧张素II(AngII)和两个强烈偏向于β-芳香素的类似物。与其他配体相比，AngII不仅在配体结合口袋的底部促进更实质性的重排，而且在受体核心的关键极性网络中也促进更实质性的重排，该网络在大多数GPCRs中形成一个钠结合部位。该区域与家族共识的分歧似乎是一个有偏见的信号开关，可能使AT1R和其他某些GPCR(如趋化因子受体)采用能够激活β-arrestin而不是异源三聚体G(Q)蛋白信号的构象。
Biased agonists of G protein-coupled receptors (GPCRs) preferentially activate a subset of downstream signaling pathways. In this work, we present crystal structures of angiotensin II type 1 receptor (AT1R) (2.7 to 2.9 angstroms) bound to three ligands with divergent bias profiles: the balanced endogenous agonist angiotensin II (AngII) and two strongly beta-arrestin-biased analogs. Compared with other ligands, AngII promotes more-substantial rearrangements not only at the bottom of the ligand-binding pocket but also in a key polar network in the receptor core, which forms a sodium-binding site in most GPCRs. Divergences from the family consensus in this region, which appears to act as a biased signaling switch, may predispose the AT1R and certain other GPCRs (such as chemokine receptors) to adopt conformations that are capable of activating beta-arrestin but not heterotrimeric G(q) protein signaling.